Affiliation: Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, Illinois 60637, USA.

ABSTRACTSystemic infection induces conserved physiological responses that include both resistance and 'tolerance of infection' mechanisms. Temporary anorexia associated with an infection is often beneficial, reallocating energy from food foraging towards resistance to infection or depriving pathogens of nutrients. However, it imposes a stress on intestinal commensals, as they also experience reduced substrate availability; this affects host fitness owing to the loss of caloric intake and colonization resistance (protection from additional infections). We hypothesized that the host might utilize internal resources to support the gut microbiota during the acute phase of the disease. Here we show that systemic exposure to Toll-like receptor (TLR) ligands causes rapid α(1,2)-fucosylation of small intestine epithelial cells (IECs) in mice, which requires the sensing of TLR agonists, as well as the production of interleukin (IL)-23 by dendritic cells, activation of innate lymphoid cells and expression of fucosyltransferase 2 (Fut2) by IL-22-stimulated IECs. Fucosylated proteins are shed into the lumen and fucose is liberated and metabolized by the gut microbiota, as shown by reporter bacteria and community-wide analysis of microbial gene expression. Fucose affects the expression of microbial metabolic pathways and reduces the expression of bacterial virulence genes. It also improves host tolerance of the mild pathogen Citrobacter rodentium. Thus, rapid IEC fucosylation appears to be a protective mechanism that utilizes the host's resources to maintain host-microbial interactions during pathogen-induced stress.

Figure 12: Lack of indicible fucosylation and SI colonization in C rodentium infected micea, C. rodentium causes no SI fucosylation in SPF mice at day 3, day 7, or day 12 p.i.b, SI colonization by C. rodentium is low regardless of Fut2 expression and LPS treatment. SI contents were removed by gentle squeezing, homogenized in PBS, and plated. Means±s.e.m; n = 4. Dotted line shows the limit of detection.

Mentions:
Importantly, LPS challenge led to the significantly increased expression of microbial virulence genes in Fut2-negative but not Fut2-sufficient mice, including RtxA (K10953) and hemolysin III (K11068) (Supplemental Information Table 2). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways potentially involved in microbial pathogenesis (defined as flagellar synthesis, chemotaxis, plant/pathogen interaction and Vibrio cholera infection) were over-represented in Fut2-deficient mice (Extended Data Fig. 7d). We hypothesized that fucosylation induced by systemic microbial challenge might limit the effects of additional exogenous or endogenous pathogens. We tested this by infecting Fut2-sufficient and Fut2-deficient mice with a non-lethal intestinal pathogen, Citrobacter rodentium. Four days after infection, mice were treated with LPS. Infected Fut2-negative mice lost significantly more weight than Fut2-sufficient animals compared to respective LPS-treated non-infected controls (Fig. 4a). Thus, infection with a non-lethal pathogen further reduced the overall fitness of Fut2-deficient mice in response to LPS. C. rodentium did not induce SI IEC fucosylation and did not colonize the SI (Extended Data Fig. 8), indicating that systemic challenge by a microbial product was required to reveal the role of inducible fucosylation.

Figure 12: Lack of indicible fucosylation and SI colonization in C rodentium infected micea, C. rodentium causes no SI fucosylation in SPF mice at day 3, day 7, or day 12 p.i.b, SI colonization by C. rodentium is low regardless of Fut2 expression and LPS treatment. SI contents were removed by gentle squeezing, homogenized in PBS, and plated. Means±s.e.m; n = 4. Dotted line shows the limit of detection.

Mentions:
Importantly, LPS challenge led to the significantly increased expression of microbial virulence genes in Fut2-negative but not Fut2-sufficient mice, including RtxA (K10953) and hemolysin III (K11068) (Supplemental Information Table 2). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways potentially involved in microbial pathogenesis (defined as flagellar synthesis, chemotaxis, plant/pathogen interaction and Vibrio cholera infection) were over-represented in Fut2-deficient mice (Extended Data Fig. 7d). We hypothesized that fucosylation induced by systemic microbial challenge might limit the effects of additional exogenous or endogenous pathogens. We tested this by infecting Fut2-sufficient and Fut2-deficient mice with a non-lethal intestinal pathogen, Citrobacter rodentium. Four days after infection, mice were treated with LPS. Infected Fut2-negative mice lost significantly more weight than Fut2-sufficient animals compared to respective LPS-treated non-infected controls (Fig. 4a). Thus, infection with a non-lethal pathogen further reduced the overall fitness of Fut2-deficient mice in response to LPS. C. rodentium did not induce SI IEC fucosylation and did not colonize the SI (Extended Data Fig. 8), indicating that systemic challenge by a microbial product was required to reveal the role of inducible fucosylation.

Bottom Line:
Fucose affects the expression of microbial metabolic pathways and reduces the expression of bacterial virulence genes.It also improves host tolerance of the mild pathogen Citrobacter rodentium.Thus, rapid IEC fucosylation appears to be a protective mechanism that utilizes the host's resources to maintain host-microbial interactions during pathogen-induced stress.

Affiliation:
Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, Illinois 60637, USA.

ABSTRACTSystemic infection induces conserved physiological responses that include both resistance and 'tolerance of infection' mechanisms. Temporary anorexia associated with an infection is often beneficial, reallocating energy from food foraging towards resistance to infection or depriving pathogens of nutrients. However, it imposes a stress on intestinal commensals, as they also experience reduced substrate availability; this affects host fitness owing to the loss of caloric intake and colonization resistance (protection from additional infections). We hypothesized that the host might utilize internal resources to support the gut microbiota during the acute phase of the disease. Here we show that systemic exposure to Toll-like receptor (TLR) ligands causes rapid α(1,2)-fucosylation of small intestine epithelial cells (IECs) in mice, which requires the sensing of TLR agonists, as well as the production of interleukin (IL)-23 by dendritic cells, activation of innate lymphoid cells and expression of fucosyltransferase 2 (Fut2) by IL-22-stimulated IECs. Fucosylated proteins are shed into the lumen and fucose is liberated and metabolized by the gut microbiota, as shown by reporter bacteria and community-wide analysis of microbial gene expression. Fucose affects the expression of microbial metabolic pathways and reduces the expression of bacterial virulence genes. It also improves host tolerance of the mild pathogen Citrobacter rodentium. Thus, rapid IEC fucosylation appears to be a protective mechanism that utilizes the host's resources to maintain host-microbial interactions during pathogen-induced stress.